tbuckley/cabot-search huggingface dataset:
Lactate metabolism as a dictator of patient outcomes and immune microenvironment in head and neck squamous carcinoma.
Authors: Xiaochuan Chen, Junping Pan, Qin Ding, Zongwei Huang, Hanxuan Yang, Sufang Qiu
Journal: Journal of Clinical Oncology (2023)

e18038 Background: Head and neck squamous cell carcinoma (HNSCC) treatment is facing clinical challenges. Recent research reports have highlighted the integral function performed by the tumor microenvironment (TME) in the prediction of clinical outcomes. Lactate metabolism mediates many cancers’ initiation and progression, including metastasis, angiogenesis and immunosuppression. However, the prognostic significance of lactate metabolism-related genes (LMRGs) and the role of TME in HNSCC requires further elucidation. Methods: We built a prognostic multigene signature with LMRGs and systematically correlated the risk signature with immunological characteristics and immunotherapy efficacy. Next, a series of single-cell sequencing analyses were used to characterize lactate metabolism in TME.The most important prognostic gene among risk signature was screened by machine learning analysis. Finally, single-cell sequencing analysis, immunofluorescence analyses, and a series of in vitro experiments were used to explore the role of PYGL in HNSCC. Results: LMRGs-related prognostic model showed good prediction performance. The immunological signaling pathways are linked to low-risk scores. Patients in low-risk group were characterized by low levels of lactate metabolism, high levels of CD8+ T cells infiltration, “hot”immune phenotype and benefit from immunotherapy. Compared with other cells, tumor cells in TME exhibited the most active lactate metabolism. Machine learning analysis highlighted that PYGL was the most important prognostic gene among risk signatures. And lactate concentrations decreased in PYGL knockdown cells. We found that PYGL was highly expressed in macrophages, may inhibit the polarization of M1 macrophages. The inflammatory phenotype was characterized by the least expression of PYGL, which was observed to be inversely linked to CD8+ T-cell infiltration, as determined by immunofluorescence analyses. Conclusions: Our study identified and validated a promising LMRGs signature associated with inflamed TME, which may accurately anticipate the survival of HNSCC patients. PYGL might be a novel biomarker to predict immune efficacy.
Prognostic effects of <i>TP53</i> variants co-occuring in patients with <i>HER2</i>-mutated non-small cell lung cancer (NSCLC).
Authors: Jamie Feng, Katrina Hueniken, Zhen (Jason) Fan, Lucy Corke, Natasha B. Leighl, Geoffrey Liu, Penelope Ann Bradbury, Adrian G. Sacher, Lawson Eng, Tracy Stockley, Ming Sound Tsao, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2023)

e21065 Background: TP53 variants are common in NSCLC and have been reported as prognostic of poor outcome. The impact of TP53 variants in ERBB2/HER2-mutated NSCLC is unclear. Methods: A total of 40 patients with HER2-mutated NSCLC at Princess Margaret Cancer Centre were identified retrospectively; next generation sequencing results were reviewed for TP53 variant status. Associations between TP53 status with patient and tumor characteristics, and outcomes (overall survival [OS] and progression-free survival [PFS]), were investigated. Median survival was computed by Kaplan-Meier estimator; differences between groups were assessed via Cox proportional hazards regression. Results: Co-occurring TP53 variants and HER2 mutations were found in 19/40 patients (47.5%). Median age was 64.5 years and most patients were female (65%), never-smokers (74%), and had adenocarcinoma (90%; Table 1). Median OS was 39.3 months (95% CI:31 months – not reached [NR]) in the TP53 wildtype (WT) cohort compared to 20.5 months (95% CI:3.7 months - NR) in the TP53 variant cohort (HR 2.65 (95% CI: 1.09-6.43; p = 0.03). Median PFS was 30.9 months [16.7-59.8] vs 15.9 months [10.2-NR], although not statistically significant (HR 1.86, 95% CI 0.83-4.18; p = 0.13). There was a tendency for presence of brain metastases at any point for those with TP53 variants (38% versus 63%, p = 0.11). Of the 29 de novo stage IV patients, 10 (36%) had first line targeted treatment. The rest had chemoimmunotherapy (29%), chemotherapy (25%) or immunotherapy (11%). Overall response rates were similar to first line palliative treatment (33% vs 38%, p = 1.00). Conclusions: Co-occuring TP53 variants with HER2 mutations are prognostic of shorter OS and PFS in NSCLC, and may be associated with a higher incidence of brain metastases. Our larger validation dataset with ~75 patients will be presented.[Table: see text]
The semantics of cancer: An experimental study in the meaning and use of cancer-related terms among surgical professionals.
Authors: Rajam Raghunathan, Jessica Rett, Rajam Raghunathan, Frederick C. Eilber
Journal: Journal of Clinical Oncology (2023)

e24216 Background: Because cancer does not form a natural kind, there is no list of properties that can exhaustively define it. Consequently, philosophers would expect the meaning of the term “cancer” to be subjective and variable, even across medical specialties. We hypothesized that a semantic difference regarding the understanding of “cancer” leads to diagnostic miscommunication. The goal of this multi-phase project is to better understand, quantify and compare expert and non-expert interpretations of the word “cancer” to help address this discrepancy. Methods: A 26-question online survey was administered to 72 English-speaking medical professionals at surgical grand rounds at the University of California, Los Angeles on October 17, 2022. Respondents were provided with 15-20 minutes to complete the survey questions, consisting of: demographics; level of experience with cancer diagnoses; a one-sentence definition of cancer; three words or phrases to describe cancer; ranking four properties as criteria for defining cancer; a short description of six conditions followed by three questions per condition on whether it qualifies as cancer, should be called “cancer,” and ought to be described as “cancer” in diagnosis delivery; ranking 10 cancers provided in order of how much they qualify as a cancer, from most to least "cancer-y." Results: Sixty-three percent of respondents were from surgical disciplines and 22% were attending surgeons. The majority (55%) reported “quite a lot of experience” with delivering cancer diagnoses. On a 7-point Likert scale from “not a cancer” (1 point) to “definitely a cancer,” no result received a 100% ranking in either category: 54% of respondents described micro-papillary thyroid carcinoma (mPTC) as “not a cancer” ( &lt; 6 points) while 53% of respondents described benign metastasizing leiomyomas as cancer ( &gt; 3 points). This suggests a widespread variation and distribution of “cancer” across subjects. While only 46% of respondents thought mPTC was “definitely a cancer,” 71% felt it should be called “cancer” ( p &lt; 0.0001). Conversely, 47% of respondents felt that benign metastasizing leiomyoma did not qualify as a cancer, but this was less significantly related to feeling that the term “cancer” should be avoided in its diagnosis delivery ( p =0.001). Conclusions: The first-phase our study presents the results obtained among surgical professionals. Variability in usage of the term “cancer” points to a gradient of understanding of what qualifies as "cancer" and in what context the term "cancer" should be used. This gradient in semantic understanding of "cancer" contributes to diagnostic miscommunication and leads to over-treatment. Future studies will focus on how different medical professionals and non-professionals understand "cancer," to mitigate misunderstanding in diagnosis and reduce over-treatment.
Real-world testing and treatment patterns among patients with stage IV non-small cell lung cancer: A retrospective observational study.
Authors: Jeffrey A. Scott, Harvey I. Katzen, Jochen K Lennerz, Melissa Lynne Johnson, Lucio N. Gordan, Robert H Dumanois, Luca Quagliata, Lauren Ritterhouse, Federico Cappuzzo, Anupama Vasudevan, Teena Sura, Sandy English, Brandon Wang, Prateesh Varughese, Rushir J. Choksi
Journal: Journal of Clinical Oncology (2023)

9030 Background: Guidelines (NCCN, CAP/IASLC/AMP) recommend clinical molecular testing of patients with advanced NSCLC to inform therapy decisions. We investigated the testing and treatment patterns of patients with stage 4 NSCLC treated in the real-world setting. Methods: This retrospective observational study included de-identified stage 4 NSCLC patients from the Integra Connect PrecisionQ database (ICD) enriched with information obtained by curation. Patients with a positive mutation for EGFR, ALK, ROS1, BRAF, MET, RET, HER2, or NTRK and who initiated treatment for stage 4 NSCLC between 01/01/2018 and 12/31/2021 were included with follow-up through 05/31/2022. Also included were demographics, ECOG score, time of ordering test, and date of death. Genomic test data were classified by method and type of test. Overall survival (OS) was calculated using Kaplan-Meier curves and data are presented using descriptive statistics. Results: Of 5195 patients in the ICD with stage 4 NSCLC, 3532 patients initiated first line of therapy (LOT1), and 2899 had somatic molecular testing ordered, specifically via tissue-based next-generation sequencing (NGS, 30%), plasma-based NGS (26%), or non-NGS methods (44%). A total of 934 patients tested positive for a driver mutation at any time during the study observation period, and 671 patients (72%) had test results available before initiating treatment. Of those treated after receiving biomarker results, 407 (61%) initiated treatment with a tyrosine kinase inhibitor (TKI), 43 (6%) with chemotherapy (chemo), 156 (23%) with chemo + immuno-oncology (IO), and 65 (10%) with IO. The median OS (95% confidence interval [CI]) was 24.46 (21.90-29.18) months for patients treated with TKI and 14.2 (11.6-16.5) months for patients treated without TKI (unadjusted hazard ratio [95% CI], 1.56 [1.26, 1.92]; P &lt; 0.001). Conclusions: Among patients with stage 4 NSCLC treated in the real-world setting, patients treated with TKI after receiving test results had better overall survival than patients treated without TKI. While subject to the limitations of a retrospective observational real-world data study, this study suggests that, with regard to utilizing genomic testing and appropriate selection of targeted treatment, adherence to treatment guidelines may improve patient outcomes. As new targeted agents continue to emerge in NSCLC, these data encourage utilization of genomic testing data to guide treatment selection. We acknowledge the significant contributions of our dear friend, Dr. Robert E. Smith, whose cheerful enthusiasm and deep expertise were a driving force of this work.
Multi-omics analysis of atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma.
Authors: Jie Dai, Lili Mao, Tianxiao Xu, Lifeng Li, Jing Lin, Guoliang Zhang, Yu Chen, Xue Bai, Caili Li, Lu Si, Jun Guo
Journal: Journal of Clinical Oncology (2023)

e21539 Background: A multicenter, open-label, single-arm phase II study has demonstrated that atezolizumab plus bevacizumab showed promising efficacy and manageable safety in patients with advanced mucosal melanoma, with an ORR of 45.0%. Here, we report the multi-omics analysis results with the aim of identifying potential biomarkers of response to this combination therapy. Methods: Patients with available samples were included in this study. The FFPE tissue was performed for DNA and RNA co-extraction and underwent whole exome sequencing (WES) and transcriptome sequencing. The responses were classified as complete response (CR) and partial response (PR) for responders and stable disease (SD) and progressive disease (PD) for non-responders per RECIST v1.1. Mutational signature, SNVs clonality, copy-number variations, differential expression genes, GSEA, and the immune microenvironment analysis were performed and analyzed for correlation with clinical benefits. Results: A total of 29 patients with FFPE samples underwent WES and/or transcriptome sequencing, including 1 CR, 15 PR, 9 SD, and 4 PD. As of January 11, 2023, the median follow-up time was 31 months (range, 5.0 to 37.0 months). Compared with non-reponders, responders had a significantly longer PFS (median 14.0, 95% CI 9.1 to 16.9 months vs 2.0, 95% CI 1.5 to 2.5 months, P&lt; 0.001) and OS (median 35.0, 95% CI 20.4 to 49.6 months vs 14.0, 95% CI 5.5 to 22.5 months, P =0.005). Of the patients who underwent WES analysis, TMB and TNB were not associated with response, PFS or OS; but 53.3% (8/15) of responders harbored NRAS/PKHDL1 mutation, whereas only 16.7% (2/12) of non-reponders harbored NRAS/PKHDL1 mutation ( P= 0.112). Transcriptome analysis revealed that compared with non-reponders, responders displayed more significant angiogenesis, T cell cytotoxicity and interferon gamma response gene expression signatures. CIBERSORT analysis showed that responsders had higher proportions of cytotoxic immune cells, and non-responders had higher a higher proportion of B cells. The expression of CD274 was not associated with the response, and the expression of CD276 was significantly higher in responders than that in non-responders ( P =0.014). Weighted gene co-expression network analysis showed that the high expression of genes associated with the p38 MAPK pathway presented in cold tumor environments ( P =0.052) and was negatively correlated to the PFS ( P&lt; 0.001) and OS ( P&lt; 0.001). Conclusions: These molecular profiles indicated that the inflammatory cell infiltration and tumor angiogenic status was associated with response to anti-PD-L1 and anti-VEGF combination treatments, and targeting p38 MAPK pathway may further improve the survival of patients with mucosal melanoma.
Safety and efficacy of ABR in pts with TN or R/R MCL: Ph Ib trial.
Authors: Tycel Jovelle Phillips, Michael Wang, Tadeusz Robak, David Gallinson, Don A. Stevens, Krish Patel, Safaa Ramadan, Chuan-Chuan Wun, Wojciech Jurczak, Stephen Douglas Smith
Journal: Journal of Clinical Oncology (2023)

7546 Background: Acalabrutinib (A) is a next-generation Bruton tyrosine kinase inhibitor approved for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Bendamustine (B) + rituximab (R) is used for treatment-naive (TN) and R/R MCL. We present updated data on safety and efficacy of ABR in patients (pts) with TN or R/R MCL. Methods: Eligible adults received ABR in this phase 1b study (NCT02717624) as follows: ABR for 6 28-d cycles, maintenance A+R for up to 2 y (TN cohort responders), then oral A continuously until progressive disease (PD) or treatment discontinuation due to toxicity (both cohorts). The primary endpoint was safety. Secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR), all per Lugano. Results: Overall, 38 pts were enrolled (TN, n=18; R/R, n=20) with median age 66 y (range, 47–86). Baseline characteristics were (TN and R/R cohorts, respectively): stage IV disease in 88.9% and 95.0%, high-risk simplified MIPI score in 11.1% and 15.0%, bulky disease &gt;5 cm in 16.7% and 30.0% or ≥10 cm in 5.6% and 10.0%, and blastoid morphology in 5.6% and 15.0%; R/R pts had a median of 2 prior lines of therapy. As of the data cutoff date (6/15/22), 6 (33.3%) TN pts and 4 (20.0%) R/R pts were receiving A monotherapy (Table). Most common any-grade AEs were nausea (n=14, 77.8%; TN) and neutropenia (n=11, 55.0%; R/R). Grade 3–4 AEs occurred in 13 (72.2%) TN pts and 17 (85.0%) R/R pts, most commonly neutropenia in both cohorts (n=7, 38.9% [TN]; n=10, 50.0% [R/R]). Serious AEs occurred in 11 (61.1%) TN pts and 13 (65.0%) R/R pts. There were no reports of ventricular tachyarrhythmia. Grade 3 atrial fibrillation occurred in 1 pt outside the safety reporting period and was not related to study treatment. Grade ≥3 major hemorrhage was reported in 2 (11.1%) TN pts and 3 (15.0%) R/R pts. Grade ≥3 hypertension was reported in 3 (16.7%) TN pts and 2 (10.0%) R/R pts. Five TN pts died (AE: pneumonitis, n=1; unknown, n=4) and 6 R/R pts died (AE: COVID and cerebrospinal meningitis, n=2; PD, n=2; unknown, n=2). ORR was 94.4% (n=17) in the TN cohort and 85.0% (n=17) in the R/R cohort, with CR rates of 77.8% (n=14) and 70.0% (n=14), respectively. Median DOR was not estimable (NE) in the TN cohort and 43.5 mo in the R/R cohort. Median PFS and overall survival were NE in the TN cohort (median follow-up 47.6 mo) and 28.6 mo and NE, respectively, in the R/R cohort (median follow-up 20.4 mo). Conclusions: Triple-combination ABR was tolerable and effective in pts with TN or R/R MCL. Clinical trial information: NCT02717624 . [Table: see text]
Demographic factors impacting time to diagnosis of diffuse large B-cell lymphoma.
Authors: Drury McAlarney, Meghan Davitt, H. Dean Hosgood, Aditi Shastri
Journal: Journal of Clinical Oncology (2023)

e18660 Background: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin’s lymphoma. Symptoms often include a palpable mass or fever; however, patients can be asymptomatic until the presentation of an oncological emergency, such as end organ complications or tumor lysis syndrome. Delayed diagnosis is related to spinal cord compression and an increased rate of complications from chemotherapy. We investigated factors impacting time until diagnosis. Methods: We performed a retrospective cohort study of DLBCL patients from the Montefiore Health System to determine how demographic factors impacted the time from initial symptom onset until diagnosis. Logistic regression models estimated the associations between race, socioeconomic status, and primary language spoken at home and increased time to diagnosis, stratified by insurance status. Odds ratios for increased time to diagnosis based on language were calculated, based on the number of participants with a time to diagnosis above the median value. Results: In a cohort of 1,076 patients that was 24.7% non-Hispanic White, 26.5% non-Hispanic Black, 7.25% Hispanic, and 41.5% “Other” as per information from Epic, the average time from symptom onset until DLBCL diagnosis was 115.76 days. Average time until diagnosis differed by race: Non-Hispanic White participants had the highest, while Hispanic participants had the lowest (188.4 vs 85.8, p = 0.03). Average age at diagnosis also differed by race: Non-Hispanic Black patients had the lowest age, whereas non-Hispanic White patients had the highest (57.3 vs. 67.4, p &lt; 0.0001). Relative to patients with a preferred language of English, patients who had a preferred language that was Spanish (adjusted OR = 1.99, 95% CI = 0.97-4.06, p = 0.059), or “other” had an increased odds ratio of increased time to diagnosis (adjusted OR = 3.15, 95% CI = 1.01-9.75, p = 0.047). Conclusions: Non-English speaking patients experienced increased time to diagnosis, with non-Spanish speaking patients experiencing an even higher increase in time to diagnosis of DLBCL. Differences by racial or ethnic group supported the finding that primary Spanish speakers experience increased times until diagnosis – Hispanic participants had a lower average time to diagnosis than other racial or ethnic groups, suggesting that the effect of language alone may be greater than this analysis suggested when race and ethnicity is controlled for. Interventions targeted at increasing resources for non-English speaking patients in our diverse patient population, such as increasing the availability of interpretation services, patient literature on preventative screenings in non-English languages, and increasing the number of healthcare workers with competency in common foreign languages, may potentially reduce DLBCL morbidity.
Validation of recurrence prediction using circulating tumor DNA in patients with curatively treated early stage non-small cell lung cancer.
Authors: Milou Schuurbiers, Christopher Gareth Smith, Koen Hartemink, Robert Rintoul, Kim Monkhorst, Daan van den Broek, Nitzan Rosenfeld, Michel van den Heuvel
Journal: Journal of Clinical Oncology (2023)

8535 Background: Stage II-III non-small cell lung cancer (NSCLC) patients receive adjuvant chemotherapy after surgery as standard-of-care treatment, despite an absolute 5-year disease free survival benefit of only 5.8%. Stage I patients do not receive adjuvant treatment but may benefit. Identification of residual disease by circulating tumor DNA (ctDNA) after curative intent therapy may allow more accurate decisions. Methods: Tumor tissue and serial plasma samples were collected from stage I-III NSCLC patients enrolled in the LEMA trial (NCT02894853). Somatic mutations identified by tumor exome sequencing were used to design patient-specific RaDaR assays, targeting up to 48 variants per patient, to analyze ctDNA in serial plasma samples. Results were compared and combined with an independent dataset (LUCID; Gale et al, Annals Oncol 2022). Results: In LEMA, 129 patients (53% stage I, 18% stage II and 29% stage III) were treated with curative intent by surgery (n=117), chemoradiation (n=8) or stereotactic radiotherapy (n=4) and followed for a median of 3.4 years. The LUCID dataset included 88 patients (49%/28%/23% in stage I/II/III). Results in the two cohorts were highly concordant (Table) and were assessed in the combined dataset of 808 serial plasma samples. Before treatment, ctDNA was detected in 22%, 72% and 90% of patients with stage I, II and III disease. ctDNA was detected post-treatment (at least one positive samples ≥14 days after the end of therapy) in 41/65 (63%) of patients who developed radiographic recurrence of their primary cancer, and preceded recurrence by a median of 204 days. For recurrence prediction by ctDNA detection post-treatment, the sensitivity, specificity, positive and negative predictive value (PPV and NPV) in stage I patients were 53%, 99%, 91% and 90%. In stage II-III patients, sensitivity was higher but specificity and NPV were lower (67%, 93%, 91% and 74%, respectively). ctDNA detection after treatment was associated with shorter recurrence-free survival (hazard ratio (HR) 11.5, P=1.8x10 -32 ) and overall survival (HR 8.1, P=1.2x10 -17 ). Conclusions: ctDNA detection by RaDaR assays predicted recurrence in two independent cohorts, confirming the potential to identify patients for adjuvant treatment. In stage I patients with positive ctDNA, adjuvant treatment could be offered with confidence due to high specificity of 99% and PPV of 91%. In stage II-III patients, the primary cancer recurred in a quarter of patients with no ctDNA detected post-treatment (NPV 74%). Our results help identify the potential role for ctDNA analysis as a decision support tool for adjuvant therapy in NSCLC. [Table: see text]